Micellar aggregation and membrane partitioning of bile salts, fatty acids, sodium dodecyl sulfate, and sugar-conjugated fatty acids: correlation with hemolytic potency and implications for drug delivery.

The co-administration of a drug with a penetration enhancer (PE) is one method by which the membrane permeability of a drug can be improved. To facilitate PE design, it is important that the molecular basis of PE toxicity and efficacy be examined, so we investigated the membrane affinity and micellar aggregation of a series of synthetic liposaccharide PEs and correlated these properties with hemolytic potency. The influence of liposaccharide alkyl chain length (nc) on the system was studied, and comparisons were made with conventional PEs such as bile salts, fatty acids, and surfactants. The liposaccharides were each synthesized in eight steps in good overall yield. Their critical micelle concentrations (CMCs) in phosphate-buffered saline ranged from 0.207 to 20.2 mM, and it was found that increasing nc by 2 afforded a 1 order of magnitude decrease in the CMC. Immobilized artificial membrane (IAM) chromatography was used to determine each PE's affinity for biological membranes, and an increase in nc caused a significant increase in the extent of membrane binding. A study of hemolytic activity revealed that liposaccharides with an nc of < or = 12 are the most likely to be biocompatible. The CMC values for all PEs showed a negative correlation with hemolytic potency; however, it was PE monomers, not micelles, that were responsible for the onset of hemolysis. The affinity of all enhancers for the IAM displayed a positive correlation with hemolytic potency, and therefore, IAM chromatography can be used to predict PE hemolytic activity. It was concluded that the biocompatibility of liposaccharides can be modulated by minor alterations in nc.